The vinca alkaloids are, in general, dimeric indoledihydroindole compounds. Two of the vinca alkaloids, vincristine and vinblastine, are obtained from the leaves of the plant Vinca rosea L. (Apocynaceae) and are marketed for the treatment of leukemias and related neoplasms in humans.
Specifically, vincristine, the chemical name for which is 22-oxovincaleukoblastine, is an antineoplastic, especially used in the treatment of acute leukemia. (C.sub.46 H.sub.58 N.sub.4 O.sub.9)
Vinblastine, the chemical name for which is vincaleukoblastine, is an antineoplastic employed in the palliative treatment of lymphomas, including generalized Hodgkin's disease, lymphosarcoma, reticulum-cell sarcoma, and advanced mycosis fungoides, and of neuroblastoma, Letterer-Siwe disease, choriocarcinoma resistent to other agents, breast carcinoma resistant to other agents, and embryonal carcinoma of the testes. (C.sub.46 H.sub.58 N.sub.4 O.sub.9)
A third vinca alkaloid is vindesine, an amide derivative of vinblastine, the chemical name for which is 23-amino-O.sup.4 -deacetyl-23-demethoxyvincaleukoblastine, is another antineoplastic. (C.sub.43 H.sub.55 N.sub.5 O.sub.7)
Vincristine, vinblastine and vindesine are described respectively in U.S. Pat. No. 3,205,220; 3,097,137; and 4,203,898. The three drugs are administered intravenously to patients suffering from susceptible neoplasms.
Standard pharmaceutical formulations of the three vinca alkaloids are lyophilized vials of the sulfate salt thereof which are reconstituted prior to use. The sulfate salts are prepared by adding the theoretical amount of sulfuric acid to a solution of the alkaloidal free base. However, in the case of vindesine, the sulfate thereof made by such procedure is not stable, and is prepared according to a procedure described in U.S. Pat. No. 4,259,242 for the lyophilized pharmaceutical formulation.
South African Patent No. 835,081 outlines the problem related to such lyophilized pharmaceutical formulations requiring reconstitution for administration, and points out the need for stable, ready-to-use solutions of vincristine sulfate and other vinca alkaloids. The problems with the lyophilized formulations mainly revolve around the extreme potency of the oncolytic, cytostatic drugs. Because of their cytostatic activity, minimizing contact with the drugs by hospital personnel and accurately calculating and administering dosages are pharmaceutical concerns of great importance. Improper reconstitution of the lyophilized formulations can create air-borne droplets hazardous to hospital personnel. Errors in calculating the quantity of diluent can result in accidental overdosages as the margin between toxic and therapeutic dosages are very small with the vinca alkaloids. See, for example, J. Pediatrics 89: 671 (1976); Cancer Chemotherapy Rept., 55: 525 (1972 and J. Pediatrics 90: 1041 (1977).
Further, the vinca alkaloids are very expensive, for example, vincristine sulfate is approximately $2000 per gram. As the lyophilized formulations of vincristine sulfate are supplied in whole milligram amounts, for example, 1 mg or 5 mg vials, whereas the dosages are actually given in decimal milligram amounts (2 mg per square meter of body surface for children and 1.4 mg per square meter of body surface for adults), only part of a vial's contents may be used for a single patient. As the recommended life for reconstituted vincristine is 14 days at refrigerated temperatures, unless the treatment facility employing the drug is a large cancer treatment center with many patients, waste of the vinca alkaloid occurs when it is necessary to discard excess reconstituted lyophilized solution that has outlasted the 14-day period.
Upon standing, the physical changes noticed for reconstituted lyophilized vincristine (reconstituted with 0.9% aqueous sodium chloride containing benzyl alcohol as a preservative) are a general haziness of solution followed by the appearance of a precipitate.
Another problem associated with reconstituted vincristine formulations is the need to incorporate a preservative in order to prevent the growth of microorganisms. Although vincristine solutions cannot generally be heat sterilized, they can be sterilized by filtration, but even if so sterilized, a preservative must be present in the diluent used to reconstitute the lyophilized material in an opened, previously sterilized liquid vial because of the possibility of contamination from the air. If it were not for the preservatives, the excess material would have to be discarded immediately and could not even be kept for the recommended maximum 14-day period.
Reconstituted solutions of vinblastine sulfate and vindesine sulfate have similar problems associated with the vincristine sulfate reconstituted solutions. However, since both vinblastine and vindesine sulfate contain an N-methyl group instead of the more labile N-formyl functionality of vincristine, stability problems thereof are not as pronounced and the recommended reconstituted stability period is for 30 rather than 14 days.
Formulations of the invention are also applicable to other vinca dimers including 4'-deoxy-1-formylleurosidine sulfate and leuroformine. The stabilized formulations of the invention are especially useful with the N-formyl vinca dimers such as vincristine or 4'-deoxy-1-formylleurosidine because they decompose by an additional mechanism, that is, by the loss of the N-formyl group, which is not a problem with the methyl containing vinblastine or vindesine.
Therefore, for the reasons outlined above, stable, ready-to-use solutions of the vinca alkaloids are required by both considerations for safety and economy. South African Patent No. 835,081 discloses aqueous pharmaceutical formulations which comprise a pharmaceutically-acceptable vinca dimer salt, a polyol, and acetate buffer, which maintains the pH of the solution between 3.0 and 5.0, and a preservative as useful, stable oncolytic preparations. Such a ready-to-use solution minimizes the contact between hospital personnel and the drug and provides a single solution strength for all the syringe sizes employed, thereby avoiding errors during reconstitution and in calculation of dosage amounts.
The present invention provides ready-to-use solutions of vinca alkaloids which are stable at room temperature and contain a citratephosphate buffer.